Invasiveness is a pathogenic phenotype of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). See e.g., Noss, E. H., and Brenner, M. B., 2008. Immunological reviews, 223:252-270; Bottini, N., & Firestein, G. S. 2013. Nat Rev Rheumatol, 9:24-33). FLS secrete components of synovial fluid and provide structural and dynamic support to the joint. In rheumatoid arthritis (RA) however, FLS assume intrinsic invasive features, and mediate destruction of cartilage and bone. For example, FLS are an abundant source of IL-6 in the joints of subjects suffering RA. FLS obtained from patients with RA and cultured ex vivo or implanted into immunodeficient mice display increased invasiveness compared to FLS from healthy subjects or patients with osteoarthritis (OA). See e.g., Bottini, N., & Firestein, G. S. 2013. Id. Targeting of FLS is being considered as an option for development of new therapies for RA. See e.g., Noss, E. H., and Brenner, M. B., 2008, Id.
Key proteins expressed by FLS include surface proteins, e.g., integrins, ICAM-1, VCAM-1, Cadherin-11, CD55, and CD90, intracellular proteins, e.g., vimentin, 6PGL, and collagen proteins, e.g., Type IV collagen and Type V collagen, as known in the art.
FLS behavior is controlled by a network of intracellular signaling pathways, many of which rely upon reversible phosphorylation of proteins on tyrosine residues. See e.g., Bottini, N., and Firestein, G. S. 2013, Id. Tyrosine phosphorylation results from the balanced action of protein tyrosine kinases (PTKs), which catalyze addition of phosphates on tyrosine residues, and phosphatases (PTPs), which counter that action by tyrosine dephosphorylation. At least 50 PTPs are expressed in FLS (Stanford, S. M. et al., 2013. Arthritis Rheum, 65:1171-1180), however little is known about the involvement of PTPs in FLS functions. To identify signaling mediators involved in promoting the unique aggressive phenotype of RA FLS, we explored the role of a PTP overexpressed in RA compared to OA FLS, PTPRK (receptor tyrosine-protein phosphatase kappa).
There are provided herein, inter alia, methods and compositions for treatment of autoimmune disease including invasiveness of FLS in RA.